Energy Calibration of Nonlinear Microcalorimeters with Uncertainty Estimates from Gaussian Process Regression.

The nonlinear energy response of cryogenic microcalorimeters is usually corrected through an empirical calibration. X-ray or gamma-ray emission lines of known shape and energy anchor a smooth function that generalizes the calibration data and converts detector measurements to energies. We argue that this function should be an approximating spline. The theory of Gaussian process regression makes a case for this functional form. It also provides an important benefit previously absent from our calibration method: a quantitative uncertainty estimate for the calibrated energies, with lower uncertainty near the best-constrained calibration points.

Absolute energies and emission line shapes of the L x-ray transitions of lanthanide metals.

We use an array of transition-edge sensors, cryogenic microcalorimeters with 4 eV energy resolution, to measure L x-ray emission-line profiles of four elements of the lanthanide series: praseodymium, neodymium, terbium, and holmium. The spectrometer also surveys numerous x-ray standards in order to establish an absolute-energy calibration traceable to the international system of units for the energy range 4 keV to 10 keV. The new results include emission line profiles for 97 lines, each expressed as a sum of one or more Voigt functions; improved absolute energy uncertainty on 71 of these lines relative to existing reference data; a median uncertainty on the peak energy of 0.24 eV, four to ten times better than the median of prior work; and six lines that lack any measured values in existing reference tables. The 97 lines comprise nearly all of the most intense L lines from these elements under broad-band x-ray excitation. The work improves on previous measurements made with a similar cryogenic spectrometer by the use of sensors with better linearity in the absorbed energy and a gold x-ray absorbing layer that has a Gaussian energy-response function. It also employs a novel sample holder that enables rapid switching between science targets and calibration targets with excellent gain balancing. Most of the results for peak energy values shown here should be considered as replacements for the currently tabulated standard reference values, while the line shapes given here represent a significant expansion of the scope of available reference data.

Are cuffless devices challenged enough? Design of a validation protocol for ambulatory blood pressure monitors at the wrist: the case of the Aktiia Bracelet.

The US and European guidelines for the diagnosis and management of hypertension recommend the introduction of systematic home and night Blood Pressure (BP) monitoring. Fully-automated wearable devices can address the needs of patients and clinicians by improving comfort while achieving measurement accuracy. Often located at the wrist and based on indirect BP measurements, these devices must address the challenges of ambulatory scenarios. New validation strategies are needed, but little guidance has been published so far.In this work, we propose an experimental protocol for the validation of cuffless wrist BP monitors that addresses ambulatory environment challenges in a controlled experimental setting. The protocol assesses the robustness of the measurement for different body postures, the ability of the device to track BP changes, and its ability to deal with hydrostatic pressure changes induced by different arm heights.Performance testing using Aktiia Bracelet is provided as an illustration. The results of this pilot study indicate that the Aktiia Bracelet can generate accurate BP estimates for sitting and lying positions and is not affected by hydrostatic pressure perturbations.Clinical Relevance- Automated cuffless BP monitoring is opening a new chapter in the way patients are being diagnosed and managed. This paper provides a guidance on how to assess the clinical utility of such devices when used in different body positions.

A Robust Principal Component Analysis for Outlier Identification in Messy Microcalorimeter Data.

A principal component analysis (PCA) of clean microcalorimeter pulse records can be a first step beyond statistically optimal linear filtering of pulses toward a fully nonlinear analysis. For PCA to be practical on spectrometers with hundreds of sensors, an automated identification of clean pulses is required. Robust forms of PCA are the subject of active research in machine learning. We examine a version known as coherence pursuit that is simple and fast and well matched to the automatic identification of outlier records, as needed for microcalorimeter pulse analysis.

A practical superconducting-microcalorimeter X-ray spectrometer for beamline and laboratory science.

We describe a series of microcalorimeter X-ray spectrometers designed for a broad suite of measurement applications. The chief advantage of this type of spectrometer is that it can be orders of magnitude more efficient at collecting X-rays than more traditional high-resolution spectrometers that rely on wavelength-dispersive techniques. This advantage is most useful in applications that are traditionally photon-starved and/or involve radiation-sensitive samples. Each energy-dispersive spectrometer is built around an array of several hundred transition-edge sensors (TESs). TESs are superconducting thin films that are biased into their superconducting-to-normal-metal transitions. The spectrometers share a common readout architecture and many design elements, such as a compact, 65 mK detector package, 8-column time-division-multiplexed superconducting quantum-interference device readout, and a liquid-cryogen-free cryogenic system that is a two-stage adiabatic-demagnetization refrigerator backed by a pulse-tube cryocooler. We have adapted this flexible architecture to mate to a variety of sample chambers and measurement systems that encompass a range of observing geometries. There are two different types of TES pixels employed. The first, designed for X-ray energies below 10 keV, has a best demonstrated energy resolution of 2.1 eV (full-width-at-half-maximum or FWHM) at 5.9 keV. The second, designed for X-ray energies below 2 keV, has a best demonstrated resolution of 1.0 eV (FWHM) at 500 eV. Our team has now deployed seven of these X-ray spectrometers to a variety of light sources, accelerator facilities, and laboratory-scale experiments; these seven spectrometers have already performed measurements related to their applications. Another five of these spectrometers will come online in the near future. We have applied our TES spectrometers to the following measurement applications: synchrotron-based absorption and emission spectroscopy and energy-resolved scattering; accelerator-based spectroscopy of hadronic atoms and particle-induced-emission spectroscopy; laboratory-based time-resolved absorption and emission spectroscopy with a tabletop, broadband source; and laboratory-based metrology of X-ray-emission lines. Here, we discuss the design, construction, and operation of our TES spectrometers and show first-light measurements from the various systems. Finally, because X-ray-TES technology continues to mature, we discuss improvements to array size, energy resolution, and counting speed that we anticipate in our next generation of TES-X-ray spectrometers and beyond.

HOLMES: The electron capture decay of [Formula: see text]Ho to measure the electron neutrino mass with sub-eV sensitivity.

The European Research Council has recently funded HOLMES, a new experiment to directly measure the neutrino mass. HOLMES will perform a calorimetric measurement of the energy released in the decay of [Formula: see text]Ho. The calorimetric measurement eliminates systematic uncertainties arising from the use of external beta sources, as in experiments with beta spectrometers. This measurement was proposed in 1982 by A. De Rujula and M. Lusignoli, but only recently the detector technological progress allowed to design a sensitive experiment. HOLMES will deploy a large array of low temperature microcalorimeters with implanted [Formula: see text]Ho nuclei. The resulting mass sensitivity will be as low as 0.4 eV. HOLMES will be an important step forward in the direct neutrino mass measurement with a calorimetric approach as an alternative to spectrometry. It will also establish the potential of this approach to extend the sensitivity down to 0.1 eV. We outline here the project with its technical challenges and perspectives.

Algorithms for Identification of Nearly-Coincident Events in Calorimetric Sensors.

For experiments with high arrival rates, reliable identification of nearly-coincident events can be crucial. For calorimetric measurements to directly measure the neutrino mass such as HOLMES, unidentified pulse pile-ups are expected to be a leading source of experimental error. Although Wiener filtering can be used to recognize pile-up, it suffers errors due to pulse-shape variation from detector nonlinearity, readout dependence on sub-sample arrival times, and stability issues from the ill-posed deconvolution problem of recovering Dirac delta-functions from smooth data. Due to these factors, we have developed a processing method that exploits singular value decomposition to (1) separate single-pulse records from piled-up records in training data and (2) construct a model of single-pulse records that accounts for varying pulse shape with amplitude, arrival time, and baseline level, suitable for detecting nearly-coincident events. We show that the resulting processing advances can reduce the required performance specifications of the detectors and readout system or, equivalently, enable larger sensor arrays and better constraints on the neutrino mass.

The Practice of Pulse Processing.

The analysis of data from x-ray microcalorimeters requires great care; their excellent intrinsic energy resolution cannot usually be achieved in practice without a statistically near-optimal pulse analysis and corrections for important systematic errors. We describe the essential parts of a pulse-analysis pipeline for data from x-ray microcalorimeters, including steps taken to reduce systematic gain variation and the unwelcome dependence of filtered pulse heights on the exact pulse-arrival time. We find these steps collectively to be essential tools for getting the best results from a microcalorimeter-based x-ray spectrometer.

Note: Operation of gamma-ray microcalorimeters at elevated count rates using filters with constraints.

Microcalorimeter sensors operated near 0.1 K can measure the energy of individual x- and gamma-ray photons with significantly more precision than conventional semiconductor technologies. Both microcalorimeter arrays and higher per pixel count rates are desirable to increase the total throughput of spectrometers based on these devices. The millisecond recovery time of gamma-ray microcalorimeters and the resulting pulse pileup are significant obstacles to high per pixel count rates. Here, we demonstrate operation of a microcalorimeter detector at elevated count rates by use of convolution filters designed to be orthogonal to the exponential tail of a preceding pulse. These filters allow operation at 50% higher count rates than conventional filters while largely preserving sensor energy resolution.

A high resolution gamma-ray spectrometer based on superconducting microcalorimeters.

Improvements in superconductor device fabrication, detector hybridization techniques, and superconducting quantum interference device readout have made square-centimeter-sized arrays of gamma-ray microcalorimeters, based on transition-edge sensors (TESs), possible. At these collecting areas, gamma microcalorimeters can utilize their unprecedented energy resolution to perform spectroscopy in a number of applications that are limited by closely-spaced spectral peaks, for example, the nondestructive analysis of nuclear materials. We have built a 256 pixel spectrometer with an average full-width-at-half-maximum energy resolution of 53 eV at 97 keV, a useable dynamic range above 400 keV, and a collecting area of 5 cm(2). We have demonstrated multiplexed readout of the full 256 pixel array with 236 of the pixels (91%) giving spectroscopic data. This is the largest multiplexed array of TES microcalorimeters to date. This paper will review the spectrometer, highlighting the instrument design, detector fabrication, readout, operation of the instrument, and data processing. Further, we describe the characterization and performance of the newest 256 pixel array.

A comprehensive classification of mandibular fractures: a preliminary agreement validation study.

This study evaluates a comprehensive classification system for mandibular fractures based on imaging analysis. The AO/ASIF scheme, defining three fracture types (A, B, C), three groups within each type (e.g. A1, A2, A3) and three subgroups within each group (e.g. A1.1, A1.2, A1.3) with increasing severity from A1.1 (lowest) to C3.3 (highest) was used. The mandible is divided into two vertical units (I and V), two lateral horizontal units (II and IV) and one central unit (III) comprising the symphyseal and parasymphyseal region. Type A fractures are non-displaced, type B are displaced and type C are multifragmentary/defect injuries. Groups and subgroups are further defined in the classification system. Two classification sessions using semi-automatic software with 7 and 9 surgeons were performed to evaluate 100 fracture cases in the first session and 50 in the second. Inter-observer reliability and individual rater's accuracy were evaluated by kappa coefficient and latent class analysis, respectively. The analysis of inter-observer agreement for the detailed coding showed kappa coefficients around 0.50 with higher agreement among raters in the vertical units. This system allows standardization of documentation of mandibular fractures, although improvement in the definition of categories and their application is required.

Gingival epithelial cells heterozygous for Toll-like receptor 4 polymorphisms Asp299Gly and Thr399ile are hypo-responsive to Porphyromonas gingivalis.

The Toll-like receptor (TLR)4 is the major sensor for bacterial lipopolysaccharide and its two common co-segregating polymorphisms, Asp299Gly and Thr399Ile, which occur at a frequency of between 6 and 10%, have been associated with infectious diseases, LPS hypo-responsiveness and cardiovascular disease. Porphyromonas gingivalis is a Gram-negative bacterium implicated in chronic periodontitis and is a known TLR4 and TLR2 agonist. We obtained two gingival epithelial cell primary cultures from subjects heterozygous for the TLR4 polymorphism Asp299Gly and compared response characteristics with similar cells from patients (four) with the wild-type TLR4 genes. Cytokine responses and transcriptome profiles of gingival epithelial cell primary culture cells to TNFalpha challenge were similar for all primary epithelial cell cultures. P. gingivalis challenge, however, gave markedly different responses for Asp299Gly heterozygous and wild-type epithelial cell cultures. The epithelial cells heterozygous for the TLR4 polymorphism Asp299Gly were functionally hypo-responsive, evidenced by differences in BD-2 mRNA expression, mRNA response profile by microarray analysis and by pro-inflammatory and chemokine cytokines at the protein and mRNA level. These findings emphasize variance in human epithelial cell TLRs, linked with Asp299Gly carriage, which results in a hypo-responsive epithelial cell phenotype less susceptible to Gram-negative diseases and associated systemic conditions.

Cardiovascular hemodynamics: relationships with insulin resistance in obese children.

We investigated blood pressure (BP), cardiac output (CO), and systemic vascular resistance (SVR) and their relationships with insulin and glucose blood levels in a group of 24 obese children (mean age, 11.9 +/- 2.1 years; 19 males). The data were compared to those obtained from a group of 19 healthy controls of the same age (12.4 +/- 2.1 years; p = NS; 13 males). BP at rest was measured and all subjects underwent an exercise testing on the treadmill (Bruce Prot.), time of exercise, maximal heart rate, maximum systolic blood pressure, CO, and SVR at rest and at peak exercise were considered. Only in the OC group were an oral glucose tolerance test were performed to calculate insulin sensitivity index (ISI) and echocardiography performed to determine the left ventricular mass (LVM). The relationships between cardiovascular and metabolic parameters were investigated. Student's t-test and linear regression analysis were used when appropriate. OC had a significant reduction in TE and higher BP, and linear regression analysis showed significant correlations between BP, ISI, and LVM. We speculate that OC need a regular cardiovascular and metabolic screening to prevent the development of early cardiovascular damage.

Involvement of protein dynamics in enzyme stability. The case of glucose oxidase.

Dynamics of glucose oxidase immobilized and in solution were compared through their tryptophan fluorescence spectra, decay times and quenching by acrylamide. Energy barrier for thermal inactivation and melting temperature of both soluble and immobilized enzyme were also measured. Data show that the fluctuation amplitude is at the origin of protein instability.

Prevention of essential hypertension in minority populations.

The precursors of essential hypertension (EH) begin in childhood. If the etiology of the evolution of EH were discovered, interventions may be developed to lead to the primary prevention of EH. In particular, one ethnic group, African-Americans (Blacks), are at increased risk of development of EH in adulthood. Hemodynamic changes in response to stressors are termed measures of cardiovascular reactivity (CVR). Ethnic difference in CVR are known to exist; are these markers or mechanisms of EH evolution? Investigations are underway to discover the mechanism(s) of the excessive vasoconstriction which appears to be characteristic of the CVR responses in Blacks. These may lead to the pharmacologic, or non-pharmacologic, interventions which may be initiated in childhood and prevent EH in adults.

Sports and marfan syndrome: awareness and early diagnosis can prevent sudden death.

Marfan syndrome is an autosomal dominant disorder of the connective tissues. Its major manifestations are in the cardiovascular, musculoskeletal, and ocular systems. Recognizing the phenotypic presentation of tall stature, long limbs and fingers, chest deformity, myopia, midsystolic click, and systolic or diastolic murmur can lead to early diagnosis. Morbidity and mortality are primarily caused by cardiovascular involvement. The goal of medical therapy is to retard the aortic root dilation that leads to sudden death from dissection or rupture. Surgical interventions for mitral valve regurgitation and resection of aortic aneurysms are highly effective. In addition, individuals with Marfan syndrome should be restricted from participation in certain sports.

Racial differences in adolescents' perceived vulnerability to disease and injury.

This study examined gender and racial differences in adolescents' risk perceptions of major diseases and motor vehicle injury and whether these perceptions agree with national mortality rates and parental health history. Adolescent (N = 135; 55% African-American) boys and girls reported on their chances compared to other adolescents of developing specific diseases or experiencing a motor vehicle injury and their knowledge of parental health history. Logistic regression models revealed that girls' risk perceptions were similar to boys' ratings even though females are at less risk than males per national figures. Caucasian adolescents inaccurately perceived that they were at significantly greater risk than African-American peers for motor vehicle injury, stroke, cancer, and heart attack. Adolescents' knowledge of a father's diabetes was predictive of greater perceived vulnerability to diabetes.

Validation of the CAS Medical Systems, inc. OscilloMitt, hand-blood-pressure cuff.

BACKGROUND: There are technical difficulties in accurately measuring blood pressure of individuals with varying arm and body sizes. OBJECTIVE: To perform validation testing with 109 children of a novel cuff that occludes the palm rather than the upper arm. METHODS: This cuff, the OscilloMitt made by CAS Medical Systems, Inc. , was used in conjunction with a commercially available monitor. Readings of blood pressure taken by trained auscultatory observers were compared with those of the OscilloMitt monitor. The mean difference in systolic blood pressure was 1.13mmHg and the mean difference in diastolic blood pressure was 0.94mmHg. The OscilloMitt was tolerated very well, especially by the young children (those aged <5years). CONCLUSION: The OscilloMitt is accurate and its use should be preferable to traditional upper-arm placement of cuffs for assessing many specific groups of patients. We recommend its use for persons aged 2 years and more.

Racial differences in the influence of body size on ambulatory blood pressure in youths.

BACKGROUND: African Americans have higher night-time blood pressures than Caucasians do despite their having similar daytime blood pressures. It is well established that body size is related to casual blood pressure. OBJECTIVE: To examine the influence of body size on racial differences in patterns of ambulatory blood pressure. METHODS: Ambulatory blood pressure recordings were performed on 292 healthy children and adolescents (148 African Americans and 144 Caucasian) aged 10-18 years (mean 13+/-2 years). These blood pressures were related to height, weight, body surface area, and body mass index in separate regression models that also included race, sex, and age as factors. RESULTS: The race-by-height interaction was significant for night-time systolic blood pressure (P<0.02), with a significant relationship for African Americans (P<0. 0001), but not for Caucasians. The race-by-weight interaction was significant for night-time systolic blood pressure (P<0.04), also with a greater relationship for African Americans (P<0.0001) than for Caucasians (P<0.03). In addition, the race-by-weight interaction was significant for night-time diastolic blood pressure (P<0.04), with a significant relationship for African Americans (P<0.01), but not for Caucasians. Finally, the race-by-body-surface-area interaction was significant for night-time diastolic blood pressure (P<0.05), again with a significant relationship for African Americans (P<0.02) but not for Caucasians. CONCLUSION: Differences in the relationship between body size and blood pressure contribute to the racial differences in patterns of ambulatory blood pressure and should be considered when evaluating patterns of blood pressure in African American youths.